The main objective of this program is to make fundamental contributions to an understanding of the molecular mechanisms responsible for cancer by investigating fundamental genetic processes involved in the control of cell growth and the maintenance of genomic stability. The projects that make up the Program collectively address a number of general issues relevant to this objective. These include the mechanisms of control of the cell cycle, control of cell growth by tumor suppressor genes, the mechanisms of DNA transposition and chromosomal rearrangement, the regulation of chromosome segregation, the role of telomerase in normal growth and tumorigenesis, and the relationship between tissue stem cells and "tumor stem cells". In addition to these mechanistic aspects, a goal is to develop important new tools for dissecting tumorigenesis. These range from technologies for disrupting gene function systematically to developing comprehensive candidate gene lists for potential tumor suppressors, to the development and exploitation of novel mouse models for the dissecting the contributions of genomic instability and dysregulation of stem cells to the genesis of cancer.